Defining the Functional Effects of Titin Gene Mutations on the Pathophysiology of Dilated Cardiomyopathy and their Clinical Significance

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Heart failure affects over 750,000 people in the UK. Dilated cardiomyopathy (DCM) is the second commonest cause and occurs in up to 1 in every 500 people. What is dilated cardiomyopathy? Dilated cardiomyopathy is a condition where the heart muscle becomes weaker (cardiomyopathy) and the heart becomes bigger (dilated). People can develop problems with fluid on their lungs, dangerous heart rhythms, and in some cases, ultimately a heart weak enough to need replacing with a transplant.In the vast majority of cases, we do not fully understand what causes the damage to the heart in the first place. This means that we do not have any targeted treatments to offer these patients. We currently use the same medicines in all patients with weak heart muscle, whatever the cause. Unfortunately, people with this condition may not have any symptoms until very advanced stages of the disease which means that the treatment we do have may not be able to do very much to repair or halt the damage to the heart. What is this research trying to achieve?Recent work done by researchers in our group, working with collaborators at Harvard University, has shown that a quarter of people who we previously thought had no identifiable cause for the weak heart, had an abnormality in a gene (called TTN) responsible for making the biggest protein in heart muscle (titin). We would like to study in more detail what it means for people who carry this gene.Who is doing this research? This work is a collaboration between the cardiac MRI imaging department at the Royal Brompton Hospital and the genetics team at the Royal Brompton and Imperial College in London. Together, Imperial College and the Royal Brompton Hospital form the largest specialist heart and lung centre in the UK. They have an internationally renowned research reputation and are best placed to conduct this research. The discovery of the abnormal gene (TTN) that forms a key part of this research was done in collaborative work by one of the research supervisors. How are we going to do this research? We would like to use an advanced scan of the heart called cardiac MRI to see if there is a pattern of disease in the heart muscle of patients with the abnormal gene. We will invite our patients who we know have both dilated cardiomyopathy and the abnormal TTN gene to have an MRI scan of their heart. MRI scans of the heart are very good at looking at the detailed structure of the heart muscle and can pick up changes that other tests (for example echocardiograms) cannot. MRI scans are safe, non invasive and painless tests. On the MRI scan, we will look for early signs of disease such as scarring in the heart - called fibrosis and abnormalities in the blood supply (microcirculation).We know that the abnormal gene can run in families so we will also invite the relatives of people with dilated cardiomyopathy to be tested for the abnormal gene. If they have the abnormal gene we will offer them the opportunity to have an MRI scan of their heart to see if they have any subtle changes in their heart, even when they do not have any symptoms. Why is this important? Crucially, once we have done the detailed MRI scan, we will also follow up the patients with dilated cardiomyopathy to see if we can identify any particular patterns in their genes or scans that are associated with a worse outcome in the long term. If this is the case, then we may be able to offer these patients earlier and more intensive treatment in the future to help prevent them from ending up with severe disease and this information might also help us to develop new treatments.For those people who feel well but have been told they have the abnormal gene, we will see if there are any early signs of heart disease on their scans. If this is the case, then in the future, we may be able to start them on the right treatment sooner to avoid progressing to advanced disease and keeping their hearts healthy.